Label: information for the user

ONIVYDEpegylated liposomal4,3mg/ml concentrated solution for infusion

irinotecán

Read this label carefully before starting to use this medication, as it contains important information for you.

• Keep this label, as you may need to refer to it again.
• If you have any questions, consult your doctor or nurse.
• If you experience any side effects, consult your doctor or nurse, even if they are not listed in this label. See section4.

What is ONIVYDE pegylated liposomal and how it works.

ONIVYDE pegylated liposomal is a cancer medication that contains the active ingredient irinotecan. This active ingredient has been introduced into small lipid particles (fats) called liposomes.

The irinotecan belongs to a group of cancer medications called "topoisomerase inhibitors". It blocks an enzyme called topoisomerase I, which is involved in the division of cellular DNA. This prevents cancer cells from multiplying and growing and, ultimately, causes these cells to die.

The liposomes are expected to accumulate within the tumor and slowly release the medication, allowing it to act for a longer period.

What is ONIVYDE pegylated liposomal used for

ONIVYDE pegylated liposomal is used to treat adult patients with metastatic pancreatic cancer (pancreatic cancer that has already spread to another part of the body) whose cancer has not been previously treated or whose previous cancer treatment contained a medication called gemcitabine.

For patients whose cancer has not been previously treated, ONIVYDE pegylated liposomal is used in combination with other cancer medications, called oxaliplatin, 5-fluorouracil, and folinic acid.

For patients previously treated with gemcitabine, ONIVYDE pegylated liposomal is used in combination with other cancer medications, called 5-fluorouracil and folinic acid.

If you have any questions about how ONIVYDE pegylated liposomal works or why you have been prescribed this medication, ask your doctor.

Follow carefully all the instructions given by your doctor. They may be different from the general information contained in this leaflet.

Do not use ONIVYDE pegylated liposomal:

• if you have a history of severe allergy to irinotecan or any of the other components of this medication (listed in section6).
• if you are breastfeeding

Warnings and precautions

Consult your doctor or nurse before receiving ONIVYDE pegylated liposomal

• if you have had any liver problems or jaundice
• if you have had any lung disease or have previously received medications (colony-stimulating factors) to increase blood cell count or radiation therapy
• if you are taking other medications (see section "Other medications and ONIVYDE pegylated liposomal")
• if you are planning to get vaccinated, as many vaccines should not be given during chemotherapy
• if you are following a low-sodium diet, as this medication contains sodium.

Consult your doctor or nurse immediately during treatment with ONIVYDE pegylated liposomal

• if you suddenly feel difficulty breathing, flushing, headache, skin rash or urticarial hives (pruritic eruption with red, inflamed bumps on the skin that appear suddenly), itching, swelling around the eyes, chest or throat tightness during infusion or shortly after
• if you have fever, chills, or other symptoms of infection
• if you have diarrhea with frequent liquid stools that do not improve after 12 to 24hours of treatment (see below)
• if you have difficulty breathing or coughing
• if you have signs or symptoms related to blood clots, such as sudden pain and swelling in a leg or arm, sudden onset of cough, chest pain, or difficulty breathing.

What to do in case of diarrhea

As soon as the first liquid stools appear, start drinking large amounts of rehydration liquids (such as water, soda, carbonated beverages, soup) to avoid losing too much liquid and electrolytes from the body. Consult your doctor immediately for proper treatment. Your doctor may give you a medication containing loperamide to start treatment at home, but do not use it for more than 48hours in a row. If loose stools persist, consult your doctor.

Blood tests and medical examinations

Before starting treatment with ONIVYDEpegylated liposomal, your doctor will perform blood tests (or other medical examinations) to determine the best starting dose for you. You will need to have blood tests (or other tests) during treatment to monitor your blood cells and evaluate how you are responding to treatment. Your doctor may need to adjust the dose or your treatment.

Children and adolescents

ONIVYDEpegylated liposomalis not recommended for use in children and adolescents under 18years.

Other medications and ONIVYDE pegylated liposomal

Inform your doctor if you are taking, have taken recently, or may need to take any other medication.

It is especially important to inform your doctor if you have previously received irinotecan in any of its forms.

Do not use ONIVYDE pegylated liposomal instead of other medications with irinotecan, as it acts differently when introduced into liposomes than when administered in its free form.

Inform your doctor, pharmacist, or nurse if you are receiving, or have received recently chemotherapy and/or radiation therapy or antifungal medication flucitosin.

Additionally, it is especially important to inform your doctor if you are also taking the following medications, as they reduce the level of irinotecan in the body:

• phenytoin, phenobarbital, or carbamazepine (medications used to treat seizures and falls)
• rifampicin and rifabutina (medications used to treat tuberculosis)
• St. John's Wort (a plant-based medication used to treat depression and fatigue)

It is especially important to inform your doctor if you are also taking the following medications, as they increase the level of irinotecan in the body:

• ketoconazole, itraconazole, or voriconazole (medications used to treat fungal infections)
• clarithromycin (antibiotic used to treat bacterial infections)
• indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir (medications for HIV infection)
• regorafenib (a medication used to treat certain types of cancer)
• telaprevir (medication used to treat a liver disease called hepatitisC)
• nefazodone (medication used to treat depression and fatigue)
• gemfibrozil (medication used to treat high levels of fat in the blood)

Use of ONIVYDE pegylated liposomal with food and beverages

Avoid eating grapefruits and drinking grapefruit juice while being treated with ONIVYDE pegylated liposomal, as they may increase the level of irinotecan in your body.

Pregnancy, breastfeeding, and fertility

Do not administer ONIVYDE pegylated liposomal if you are pregnant, as it may harm the fetus. Inform your doctor if you are pregnant or think you may be pregnant. If you intend to become pregnant, consult your doctor. If you are given ONIVYDE pegylated liposomal, do not breastfeed for one month after the last dose.

Before starting to use this medication, consult your doctor about the possible risk of this medication and the options that may preserve your ability to have children.

During treatment with ONIVYDE pegylated liposomal and for the seven monthsfollowing, choose an effective method of birth control that is suitable for you, in order to avoid pregnancy during this period. Men should use condoms during treatment with ONIVYDE pegylated liposomal and for 4months after completing treatment.

Inform your doctor if you are breastfeeding. Do not administer ONIVYDE pegylated liposomalif you are breastfeeding, as it may harm the baby.

Driving and operating machinery

ONIVYDE pegylated liposomal may affect your ability to drive and operate machinery (as you may feel drowsy, dizzy, or exhausted with the use of ONIVYDE pegylated liposomal). If you feel drowsy, dizzy, or exhausted, you should avoid driving, operating machinery, or performing other tasks that require maximum attention.

ONIVYDE pegylated liposomalcontains sodium

This medication contains 33.1 mg of sodium (main component of table salt/for cooking) in each vial. This is equivalent to 1.65% of the maximum daily sodium intake recommended for an adult.

Only healthcare professionals with experience in administering cancer medications can administer ONIVYDE pegylated liposomal

Follow carefully all instructions provided by your doctor or nurse

Your doctor will decide the doses to be administered

ONIVYDE pegylated liposomal is administered as a single dose in the form of an infusion (drip) into a vein, which must last at least 90 minutes

If your cancer has not been previously treated, after administering ONIVYDE pegylated liposomal, you will be administered three other medications, oxaliplatino, ácido folínico, and 5-fluorouracilo

If your cancer has been previously treated with a medication called gemcitabina, once ONIVYDE pegylated liposomal has been administered, you will be administered two other medications, ácido folínico and 5-fluorouracilo

Treatment will be repeated every two weeks

In certain cases, it may be necessary to reduce doses or prolong administration intervals

You may receive premedication for nausea and vomiting. If you have experienced sweating, abdominal cramps, and salivation, as well as frequent early diarrhea during previous treatments with ONIVYDE pegylated liposomal, you may receive other medications before ONIVYDE pegylated liposomal to prevent or reduce these effects in subsequent treatment cycles

If you have any other questions about the use of this medication, ask your doctor or nurse

Like all medicines, this medicine can cause side effects, although not everyone will experience them. It is important that you know which side effects may occur.

Your doctor may also prescribe other medicines to help control side effects.

Inform your doctor or nurse immediately if you experience any of the following severe side effects:

• If you experience swelling under the skin (angioedema) and/or symptoms of possible anaphylactic/anaphylactoid reactions such as sudden difficulty breathing, flushing, nausea, headache, skin rash or urticarial hives (a pruritic rash with red, inflamed bumps on the skin that appear suddenly), itching, swelling around the eyes, chest or throat tightness during infusion or shortly after. Severe allergic reactions can be fatal. It may be necessary to stop the infusion and administer treatment or monitor side effects.
• If you have fever, chills, and signs of infection (as you may need immediate treatment)
• If you experience intense and persistent diarrhea (liquid stools and frequent bowel movements); see section 2

The following other side effects may occur:

Very common (may affect more than 1 in 10 people)

Laboratory test changes

• Low white blood cell counts (neutropenia and leucopenia), low red blood cell counts (anemia)
• Low platelet counts (thrombocytopenia)
• Low levels of salts in the body (e.g., potassium, magnesium)

Stomach and intestines

• Diarrhea (frequent, soft, or watery stools)
• Nausea and vomiting
• Abdominal pain or intestinal pain
• Mouth pain (in the mouth)
• Swelling of the digestive tract lining (mucosal inflammation)

General

• Weight loss
• Loss of appetite
• Fluid loss from the body (dehydration)
• Generalized weakness and fatigue
• Abnormal fluid retention in the affected tissues (edema)
• Fever

Skin

• Unusual hair loss

Nervous system

• Dizziness
• Nerve damage in arms and legs causing pain or numbness, tingling, and burning (peripheral neuropathy)
• Paresthesia, a sensation of numbness, tingling
• Bad taste in the mouth

Common (may affect up to 1 in 10 people)

Laboratory test changes

• Low lymphocyte counts (linfopenia), a type of white blood cell important for the immune system
• Low blood sugar (hypoglycemia)
• Abnormally low albumin levels (a protein important in the body)
• Increased liver enzymes (alanine aminotransferase or aspartate aminotransferase or gamma-glutamyltransferase) in blood tests
• High levels of alkaline phosphatase in the blood, a protein that contributes to certain chemical processes in the body and is found in many parts of the body. Elevated levels of alkaline phosphatase in the blood may indicate liver or bone disorders.
• Increased bilirubin levels (a yellow-orange pigment, a product of normal breakdown of red blood cells) in other laboratory tests related to liver function
• Increased levels in other laboratory tests (increased international normalized ratio) related to blood clotting
• Increased creatinine levels in the blood, a product that shows that the kidneys are not functioning well

Stomach and intestines

• Gastroenteritis, inflammation of the stomach and intestines
• Colitis, inflammation of the intestines that causes diarrhea (enterocolitis), gas, abdominal swelling
• Indigestion
• Constipation
• Esophageal reflux disease (GERD), a condition where stomach acid flows up into the esophagus
• Dysphagia, difficulty swallowing
• Hemorrhoids
• Dry mouth

General

• Chills
• Lack of sleep
• Abnormal reaction to infusion causing symptoms such as difficulty breathing, flushing, headache, chest or throat tightness.
• Fast heart rate
• Blurred vision
• Headache

Skin

• Itching
• Dry skin
• Rash
• Hand and foot syndrome: redness, swelling, and/or pain in the palms of the hands and/or soles of the feet
• Darker skin patches (hyperpigmentation)

Nervous system

• A syndrome called "cholinergic syndrome," with sweating, salivation, and abdominal cramps
• Toxicity causing neurological disorders
• Unpleasant and abnormal sensation to the touch
• Tremors

Infections

• Infections, for example, fungal infections in the mouth (oral candidiasis), fever with low neutrophil counts in white blood cells (neutropenic fever), infections related to the administration of the medicine through a vein
• Potentially fatal complication of the body's reaction to an infection (septic shock)
• Pneumonia, an infection of the lungs
• Urinary tract infection

Blood vessels

• Low blood pressure (hypotension)
• Thromboembolic events, formation of a blood clot in a blood vessel (vein or artery) or obstruction of the main pulmonary artery or one of its branches (pulmonary embolism), or obstruction due to a blood clot in another part of the circulatory system (embolism).

Lungs and respiratory tract

• Decline in voice, hoarse or excessively raspy voice
• Shortness of breath
• Inflammation of the nose and throat
• Hiccup
• Nasal bleeding

Kidneys

• Sudden renal function problems that may cause renal deterioration or loss of renal function

Muscles

• Weakness, muscle pain, abnormal muscle contractions

Uncommon (may affect up to 1 in 100 people)

Laboratory test changes

• Low counts of all types of blood cells (pancytopenia)
• Hemolytic anemia, excessive destruction of red blood cells
• Increased monocytosis, increased blood levels of monocytosis (a type of white blood cell)
• Increased blood levels of troponin I, a protein that indicates heart damage
• Decreased total protein levels, decreased blood protein levels related to renal or hepatic function or poor absorption
• Decreased renal clearance of creatinine, decreased creatinine clearance, showing that the kidneys are not functioning correctly
• Excess protein in the urine
• Abnormal levels of salts in the blood
• Low blood chloride levels (hypochloremia)
• Elevated blood uric acid levels that cause symptoms, especially painful inflammation in the joints (gout)
• Elevated blood sugar levels (hyperglycemia)
• Iron deficiency in the blood

Stomach and intestines

• Inflammation of the esophagus (the tube that carries food to the stomach)
• Inflammation of the rectal mucosa (the final part of the large intestine)
• Obstruction of the part of the intestine that exits the stomach (duodenal obstruction)
• Abnormal muscle contractions in the esophagus (the tube that carries food from the mouth to the stomach)
• Loss of intestinal muscle movement (ileus)
• Loss of bowel control (incontinence), anal tear, difficulty defecating (pain, effort, or obstructed defecation)
• Bleeding through the anal canal (hematochezia)
• Rectal bleeding
• Painful ulcers in the mouth (aphthous ulcers), abnormal and unpleasant sensation in the mouth, numbness, tingling in the mouth, inflammation of the mouth corners (oral commissures), loss or erosion of mouth tissue (oral ulceration)
• Tongue disorder
• Dental caries, gum disorder, gum disease, increased sensitivity of the teeth, severe gum inflammation
• Stomach disorder, inflammation of the stomach lining (gastritis)
• Belching
• Diverticulitis, a disease that affects the intestine

General

• Allergic reaction to the active ingredient or excipients
• Irritation of the eyes, reduced visual acuity, conjunctivitis, redness, and discomfort in the eye
• Dizziness, spinning sensation
• General feeling of discomfort
• General decline in physical health
• Red, painful, and often swollen area on the body (inflammation)
• Failure of one or more organs at the same time
• Anomalies in temperature sensation, body temperature below 35°C (hypothermia)
• Swelling of the lips and face
• Symptoms similar to the flu, such as high fever, sore throat, runny nose, cough, and chills
• Inadequate nutrition
• Fluid retention around the tumor
• Excessive sweating
• Coldness in the extremities

Skin

• Urticarial hives (red, inflamed bumps)
• Toxicity causing nail disorders, change in nail plate color (nails)
• Cutaneous lesion, skin redness (erythema), dry skin, sensitive skin
• Pustular rash with lesions filled with pus
• Dermatitis with blisters (dermatitis bullous)
• Generalized exfoliative dermatitis, skin peeling or shedding
• Petechiae, small blood spots under the skin and telangiectasia, small red, linear blood vessels visible
• Psoriasis, an inflammatory disease causing red, scaly patches on the skin
• Vulvar and vaginal dryness

Nervous system

• Seizure
• Bleeding in the brain (hemorrhage), sudden interruption of blood flow to the brain caused by obstruction of blood supply to a part of the brain (ischemic stroke), temporary interruption of blood flow to the brain (transient ischemic attack)
• Loss of smell (anosmia), loss of taste functions of the tongue (ageusia)
• Unsteadiness or dizziness (balance disorder)
• Excessive somnolence
• Decreased sensitivity to touch, pain, and temperature
• Limitations in cognitive function and abilities (intellectual disability) and unusual lack of energy and mental acuity (lethargy)
• Reduced ability to memorize things
• Sensation of impending and transient loss of consciousness (presyncope) and fainting (syncope)
• Confusion
• Neurosis (a mental disorder with high levels of anxiety) and depression

Infections

• Systemic inflammation of the body, caused by a gallbladder infection and bile ducts (biliary sepsis)
• Fever caused by an infection
• Bacterial infection caused by a bacterium called Clostridium difficile
• Mucosal infection (infection of the lining of body cavities)
• Boil, a bacterial infection of the hair follicles
• Laryngitis, an infection of the larynx
• Sinusitis, an inflammation of the paranasal sinuses
• Dental infection
• Fungal infection of the mouth
• Herpes simplex, a viral infection of the mouth (such as febrile herpes) or genitals
• Vulvovaginal mycotic infection
• Anal abscess, an inflamed anal area where pus has accumulated

Lungs and respiratory tract

• Decreased availability of oxygen in body tissues or increased supply of oxygen to body tissues and organs
• Cough
• Inflammation of the nose
• Complete or partial collapse of a lung (atelectasis)
• Inflammation of the lungs (pneumonitis, interstitial lung disease)

Pain

• Pain, non-cardiac chest pain, arm pain, joint pain, back pain, bone pain, pain in an extremity, pain and inflammation in multiple joints (polyarthritis), pain in the mouth and throat (oropharyngeal pain)
• Chest pain
• Mouth pain (paresthesia oral)
• Gum pain
• Painful urination

Heart and blood vessels

• Angina pectoris - Chest pain, jaw pain, and back pain, caused by physical exertion and due to problems with blood flow to the heart.
• Heart attack
• Strong heartbeat that may be fast or irregular
• Abnormal heart rhythm activity that affects its rate (prolongation of the QT interval in the electrocardiogram)
• High blood pressure (hypertension)
• Inflammation of a vein (phlebitis)
• Accumulation of blood under the skin (hematoma)

Liver

• Inflammation of the bile duct, usually caused by bacteria (cholangitis)
• Inflammation of the liver as a reaction to certain substances
• Reduced bile flow from the liver due to obstruction (cholestasis)
• Hepatic cytolysis, liver inflammation with increased levels of transaminases, liver enzymes that indicate liver function.

Reporting side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the national notification system included in theAppendix VBy reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging and vial after CAD. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2 °C and 8 °C).

Do not freeze.

Store the vial in the outer packaging to protect it from light.

Once the concentrate for infusion has been diluted with a 5% glucose injectable solution or sodium chloride 9 mg/ml (0.9%), the dispersion must be used as soon as possible, but it can be stored at room temperature (between 15 °C and 25 °C) for a period of up to 6 hours. Before use, the diluted infusion dispersion can be stored in the refrigerator (2 °C-8 °C) for a period not exceeding 24 hours. It must be protected from light and not frozen.

This medication should not be disposed of through the drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. This will help protect the environment.

Composition of ONIVYDE pegylated liposomal

• The active ingredient is irinotecan. A vial of 10 ml of concentrate contains 43 mg of irinotecan anhydrous base (in the form of sucrosofate salt in a pegylated liposomal formulation).
• The other components are:1,2‑distearoil‑sn‑glicero‑3‑fosfocolina(DSPC); cholesterol, N‑(carbonil‑metoxipolietilenglicol‑2000)‑1,2‑distearoil‑sn‑glicero‑3‑fosfoetanolamina (MPEG‑2000‑DSPE); octosulfato de sacarosa; ácido2‑[4‑(2‑hidroxietil)-1-piperacinil-(1)] etanosulfónico(tampón HEPES); cloruro de sodio and water for injection. ONIVYDE pegylated liposomal contains sodium; if you follow a low-sodium diet, see section2.

Appearance of the product and contents of the pack

ONIVYDE pegylated liposomal is supplied as an isotonic, opaque, white to slightly yellowish liposomal dispersion in a glass vial.

Each pack contains a vial with10ml of concentrate.

Marketing authorisation holder

Les Laboratoires Servier

50, rue Carnot

92284 Suresnes cedex

France

Manufacturer

Ipsen Pharma Biotech

Parc d’Activités du Plateau de Signes

Chemin Départemental 402

83870 Signes

France

Les Laboratoires Servier Industrie

905 Route de Saran

45520 Gidy

France

You can request more information about this medicine by contacting the local representative of the marketing authorisation holder:

Last update of this leaflet: September 2024

The detailed information about this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu.

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This information is intended solely for healthcare professionals:

Preparation and administration of ONIVYDE pegylated liposomal

• ONIVYDEpegylated liposomalis supplied as a sterile liposomal dispersion in a concentration of4,3mg/ml and must be diluted before administration using a needle of gauge not greater than 21. Dilutewith a glucose injection solution5%or a sodium chloride injection solution9mg/ml (0,9%) to prepare a dispersion of the corresponding dose of ONIVYDEpegylated liposomaldiluted to a final volume of500ml. Mix the diluted dispersion gently.
• In the first-line treatment of metastatic pancreatic adenocarcinoma, ONIVYDE pegylated liposomal must be administered before oxaliplatin, followed by folinic acid, followed by 5-fluorouracil.
• In the treatment of metastatic pancreatic adenocarcinoma in patients who have progressed after a gemcitabine-based therapy, ONIVYDE pegylated liposomal must be administered before folinic acid, followed by5‑fluorouracil.
• ONIVYDE pegylated liposomal must not be administered by rapid intravenous injection or as an undiluted dispersion.
• Aspirate techniques must be used during the preparation of the infusion. ONIVYDEpegylated liposomalis only for single use.
• From a microbiological point of view, the medicine must be used as soon as possible after dilution. Before use, the diluted infusion dispersion may be stored at room temperature(between 15°Cand25°C)for a period of up to 6hours or in the refrigerator(2°C‑8°C) for a period not exceeding 24hours.Protectfrom light and do not freeze.
• Care must be taken to avoid extravasation and the infusion site must be monitored for signs of inflammation. In case of extravasation, it is recommended to wash the area with a sodium chloride injection solution9mg/ml (0,9%) and/or sterile water and apply ice.

Handling and disposal of ONIVYDE pegylated liposomal

• ONIVYDEpegylated liposomalis a cytotoxic medicine and must be handled with caution. It is recommended to use gloves, glasses, and protective clothing during the handling or administration of ONIVYDEpegylated liposomal. If the dispersion comes into contact with the skin, the skin must be washed thoroughly with water and soap immediately. If the dispersion comes into contact with mucous membranes, they must be washed thoroughly with water. Due to the cytotoxic nature of the medicine, pregnant women must not handle ONIVYDEpegylated liposomal.
• The disposal of unused medicine and all materials that have come into contact with it must be carried out in accordance with local regulations.